In order to optimize the risk-benefit and cost-effectiveness of colonoscopy for colorectal cancer (CRC) screening, risk-stratification is of paramount importance. Exploitation of the "field effect" in which readily accessible colonic mucosa (i.e. rectum) should reflect the neoplastic risk throughout the colon, is an attractive proposition. However, current markers such as distal/rectal adenomas and aberrant crypt foci (ACF) lack the sensitivity and predictive value for clinical utility. We have recently developed four-dimensional elastic light scattering "fingerprinting" (4D-ELF), a biomedical optics technology that allows us to gather heretofore unattainable quantitative information about nano/micro-architecture of living epithelia in situ. Using 4D-ELF, we discovered several spectral signatures in histologically normal mucosa that preceded all conventional biomarkers of CRC and served as one of the earliest markers of the "field effect" in experimental models of colon carcinogenesis. Indeed, rectal spectral markers had unprecedented sensitivity, specificity, positive and negative predictive values for neoplastic risk. Pilot studies confirmed the relevance of these spectral markers to humans. The proposed project will test the hypothesis that rectal spectral markers can predict the occurrence of concurrent and future colonic neoplasia. In this application, we propose to construct an endoscopically compatible 4D-ELF probe in order to assess performance characteristic of prediction rules of rectal spectral markers (established and novel) for neoplasia detected on colonoscopy in average risk patients. We will also ascertain the ability of spectral markers to predict future neoplasia by evaluating rectal ACF number and adenoma occurrence in surveillance endoscopies of patients undergoing CRC resection. Finally, we will perform initial studies to understand the biological basis of spectral markers. In the future, spectral markers may be assayed with a 4D-ELF probe during a routine rectal examination (without the need for bowel preparation or colonoscopy) thus providing a practical and accurate means of determining the optimal CRC screening regimen, such as the need for colonoscopy.